The urokinase (uPA)-uPA receptor (uPAR) system is implicated in the pathogenesis of pulmonary inflammation and neoplasia via proteolytic remodeling, nonproteolytic signaling and regulation of cell migration and mitogenesis. In patients with acute lung injury (All), depressed uPA-mediated fibrinolytic activity promotes alveolar fibrin deposition, favoring accelerated fibrotic repair. We recently demonstrated that lung epithelial cells regulate both uPA and uPAR at the posttranscriptional level of mRNA stability. We hypothesize that expression of uPA and uPAR by lung epithelial cells is regulated via these newly appreciated posttranscriptional pathways to influence epithelial cell responses germane to All and its repair. Our objective is to elucidate these pathways. These pathways are poorly understood at this time, representing an important gap in our understanding of the pathogenesis of ALL Our preliminary data support the hypothesis and show that phosphoglycerate kinase (PGK) and other newly appreciated uPAR and uPA mRNA binding protein-mRNA interactions control uPAR and uPA expression by lung epithelial cells. Our Specific Aims are: 1) To determine how PGK and another newly recognized uPAR mRNA coding region binding protein regulate uPAR expression in lung epithelial cells. 2) To elucidate the role of newly recognized 3'-untranslated region (3'UTR) uPAR mRNA-binding protein interactions on uPAR expression. 3) To determine mechanism(s) by which PGK and hnRNPC, another putative regulatory protein, regulate cytokine mediated expression of uPAR in lung epithelial cells. 4) To clone the cDNA for the uPA mRNABp and determine how it regulates uPA expression in lung epithelial cells. These studies will extend our - understanding of mechanisms by which lung epithelial cells regulate uPAR and uPA expression and hasten the development of novel therapeutics for ALI and its repair.